Is PTPRO p.Val49Ile (c.145G>A) pathogenic?

PTPRO p.Val49Ile (c.145G>A) is classified Likely benign in PTPRO (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-20). AlphaMissense: likely benign (0.0712); Very rare (popmax 0.00667%, amr).

How common is PTPRO p.Val49Ile (c.145G>A) in the general population?

PTPRO p.Val49Ile (c.145G>A) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about PTPRO p.Val49Ile (c.145G>A)?

AlphaMissense predicts likely benign (score 0.0712) — an in-silico prediction, not a clinical call.

PTPRO p.Val49Ile

c.145G>A · VCV3428216

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0712 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0712	likely benign
REVEL	0.023	moderately benign-leaning
SaProt	LLR -6.69	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.18	GERP -4.6, phastCons 0.018
Regional constraint	o/e 0.93	unconstrained · MANE · 258 kb · p 0.015 · regional, not allelic
Overall
CADD	0.932	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/60,000 alleles

Filtering AF 0.00318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00286%

Overall 0.00403% 65/1,613,596 alleles · very rare exomes 59/1,461,416 · genomes 6/152,180 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.008%	12,498
Admixed Americangrpmax	0.00667%	15,000
South Asian	0.00439%	22,766
European (non-Finnish)	0.00415%	24,073
African / African-American	0.004%	25,004

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PTPRO
Protein: p.Val49Ile
Coding: c.145G>A
MANE Select: NM_030667
Type: single nucleotide variant
Location: chr12:15484043 (GRCh38)
Gene constraint: LOEUF 0.513 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 77.55 · 2 PDB

Full PTPRO gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PTPRO p.Ala1086Val Uncertain significance ★★ ⚠ same type
PTPRO p.Ala591Thr Uncertain significance ★★ ⚠ same type
PTPRO p.Arg480Trp Uncertain significance ★★ same type
PTPRO p.Arg607Gln Uncertain significance ★★ ⚠ same type
PTPRO p.Asn569Asp Uncertain significance ★★ ⚠ same type
PTPRO p.Asp162Val Uncertain significance ★★ ⚠ same type
PTPRO p.Asp301His Uncertain significance ★★ ⚠ same type
PTPRO p.Asp799Gly Uncertain significance ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ptpro-p-val49ile (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown